The success of cisplatin and its derivatives as anticancer agents has stimulated the development of metal-based compounds, including that of gold, for anticancer treatment [C. F. Shaw III, Chem. Rev. 1999, 99, 2589]. In this context, extensive investigations on the biological properties of gold(I) and gold(III) have been reported. The development of gold(III) compounds as potential anti-cancer agents has been hampered by their poor stability in solution. Very few cytotoxic gold(III) compounds such as [Au(bipyc-H)(OH)][PF6] (bipyc-H=deprotonated 6-(1,1-dimethylbenzyl)-2,2′-bipyridine), [Au(dmamp)Cl2] [dmamp=2-(dimethylaminomethyl)phenyl], and gold(III) Tetraarylporphyrins [C.-M. Che, R. W.-Y. Sun, W.-Y. Yu, C.-B. Ko, N. Zhu, H. Sun, Chem. Commun. 2003, 1718], have been reported to have significant stability.
The stability of metal compounds is usually enhanced by multi-dentate chelating ligands. Lippard and co-workers first reported the use of the tridentate terpyridine ligand (terpy) to generate a planar gold(III) metallointercalator [L. S. Hollis, S. J. Lippard, J. Am. Chem. Soc. 1983, 105, 4293]. Messori, Orioli and Coronnello also reported a number of gold(III) compounds containing 6-(1,1-dimethylbenzyl)-2,2′-bipyridine ligands [M. Coronnello, B. Mini, B. Caciagli, M. A. Cinellu, A. Bindoli, C. Gabbiani, L. Messori, J. Med. Chem. 2005, 48, 6761; L. Giovagnini, L. Ronconi, D. Aldinucci, D. Lorenzon, S. Sitran, D. Fregona, J. Med. Chem. 2005, 48, 1588]. Guo and co-workers recently reported the synthesis of [Au(Quinpy)Cl]Cl [where HQuinpy=N-(8-quinolyl)pyridine-2-carboxamide] and its derivatives. These gold(III) compounds are cytotoxic and bind to DNA [T. Yang, C. Tu, J. Zhang, L. Lin, X. Zhang, Q. Liu, J. Ding, Q. Xu, Z. Guo, Dalton Trans. 2003, 3419]. In addition, Coronnello, Messori and Fregona and their co-workers have recently shown that gold(III) induced cytotoxicity may proceed via an induction of apoptosis.
The synthesis and study of a series of gold(III) porphyrins that exhibit potent in vitro and in vivo anti-cancer properties toward hepatocellular carcinoma and nasopharyngeal carcinoma has been reported. As demonstrated by DNA microarray and proteomic analyses, the gold(III) tetraarylporphyrins up-regulated the transcription and translation of a number of apoptosis-related gene and protein expressions. [Aum(CNC)mL]n+ compounds (where HCNCH=2,6-diphenylpyridine, and L=phosphine-containing ligand, Scheme 1), were first developed and reported in 1998 [K.-H. Wong, K.-K. Cheung, M. C.-W. Chan, C.-M. Che, Organometallics 1998, 17, 3505].
It is an object of the present invention to provide gold(III)porphyrins which are more robust in solution and therefore more effective in treatment of tumors.